Intramolecular 4 + 3 cycloadditions. Aspects of stereocontrol in the synthesis of cyclooctanoids. A synthesis of (+)-dactylol

Article abstract of DOI:10.1021/ol006390b

The judicious placement of stereocenters on precursors for 4 + 3 cycloaddition reactions can lead to high levels of stereocontrol in the 4 + 3 cycloaddition process of cyclopentenyl cations and tethered butadienes. This concept was successfully tested in the context of a synthesis of (+)-dactylol.

Full text of DOI:10.1021/ol006390b

ORGANIC
LETTERS
2
000
Vol. 2, No. 18
913-2915
Intramolecular 4 + 3 Cycloadditions.
Aspects of Stereocontrol in the
Synthesis of Cyclooctanoids. A
2
†
Synthesis of (+)-Dactylol
Michael Harmata* and Paitoon Rashatasakhon
Department of Chemistry, UniVersity of MissourisColumbia,
Columbia, Missouri 65211
harmatam@missouri.edu
Received July 28, 2000
ABSTRACT
The judicious placement of stereocenters on precursors for 4 + 3 cycloaddition reactions can lead to high levels of stereocontrol in the 4 +
cycloaddition process of cyclopentenyl cations and tethered butadienes. This concept was successfully tested in the context of a synthesis
3
of (+)-dactylol.
The intramolecular 4 + 3 cycloaddition (I4/3C) of allylic
cations and dienes provides a rapid access to complex
carbocyclic products from relatively simple starting materi-
sodium trifluoroethoxide in trifluoroethanol afforded the 4
+ 3 cycloadduct 2 in 61% yield as a 1:1 mixture of endo/
4
exo isomers (Scheme 1). Analogously, treatment of 3 with
1
2
3
als. Some time ago, both our group and the West group
published data supporting the concept that the intramolecular
+ 3 cycloaddition reaction of certain cyclopentenyl cations
with tethered butadienes or furans could lead to 5-8 and
4
Scheme 1
5-8-5 ring systems. For example, treatment of 1 with
†
This paper is dedicated to Professor Norman Rabjohn on the occasion
of his 85th birthday.
(
1) For recent reviews of 4 + 3 cycloaddition chemistry, see: (a)
Harmata, M. Tetrahedron 1997, 53, 6235. (b) Harmata, M. In AdVances in
Cycloaddition; Lautens, M., Ed.; JAI: Greenwich, 1997; Vol. 4, pp 41-
6. (c) Harmata, M. In Recent Research DeVelopments in Organic
8
Chemistry; Transworld Research Network: Trivandrum, 1997; Vol. 1, pp
23-35. (d) Rigby, J. H; Pigge, F. C. Org. React. 1997, 51, 351. (e) Cha,
J.; Oh, J. Curr. Org. Chem. 1998, 2, 217.
2) Harmata, M.; Elahmad, S.; Barnes, C. L. J. Org. Chem. 1994, 59,
241.
3) (a) West, F. G.; Hartke-Karger, C.; Koch, D. J.; Kuehn, C. E.; Arif,
5
titanium tetrachloride afforded the cycloadducts 4a and 4b
as a 2.7:1 mixture of stereoisomers (Scheme 2). The poor
stereochemical control observed in these types of reactions
appears to be fairly general and creates barriers to the
application of the methodology in synthesis. As part of our
continuing studies in this area, we are attempting to develop
(
1
(
A. M. J. Org. Chem. 1993, 58, 6795. (b) Wang, Y.; Arif, A. M.; West, F.
G. J. Am. Chem. Soc. 1999, 121, 876.
(
4) Harmata, M.; Elomari, S.; Barnes, C. L. J. Am. Chem. Soc. 1996,
1
18, 2860.
1
0.1021/ol006390b CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/05/2000

forms of this compound have been reported, essentially as
demonstrations of methodology capable of producing 5-8
Scheme 2
8
fused ring systems. Only one of these syntheses involved a
8
e
cycloaddition process. Our retrosynthesis is shown in
Scheme 4. Functional group manipulation of 8 was antici-
pated to lead to (+)-dactylol.
Scheme 4
strategies which will enable high levels of stereochemical
control in reactions of this class. This report details some of
our recent success in achieving our goals.
Our approach in performing highly stereoselective I4/3C
reactions with cyclopentenyl cations was based on precedent
established in both inter- and intramolecular 4 + 3 cyclo-
addition reactions. It is known that cyclopentenyl and
cyclohexenyl cations bearing a stereogenic center react with
dienes from their least-hindered faces, that is, on the face
5
opposite the substituent. In addition, Giguere and co-workers
have established a dramatic effect of a dienylic substituent
on the stereochemical outcome of an intramolecular 4 + 3
6
cycloaddition reaction. This group reported that treatment
of 5 with triflic anhydride at low temperature was shown to
afford 6 as the major product of the reaction (isomer ratio:
We speculated that 8 could be obtained by cycloaddition
of chloroketone 9. The oxyallylic cation produced by the
heterolysis of the corresponding enol or enolate was expected
to cyclize via the transition state described by 12 (Figure
92:5:3) (Scheme 3).
1), in accordance with the precedent discussed. The cycload-
Scheme 3
We decided to explore the combination of these two
stereochemical factors in the context of intramolecular 4 +
cycloaddition reactions of a cyclopentenyl cation. It soon
Figure 1.
3
became apparent that the natural product (+)-dactylol
appeared to provide the ideal platform around which to
conduct the study.
dition precursor was expected to be formed from the
enantiomerically pure ketoester 10, prepared in a straight-
(
+)-Dactylol is a cyclooctanoid sesquiterpene isolated
9,10
forward fashion from (R)-pulegone, and iododiene 11. This
7
from the sea hare Aplysia dactylomela. A small number of
meant using the stereogenic methyl-bearing center in 10 to
effect stereocontrol. Although the stereogenic center on the
five-membered ring would ultimately be destroyed to produce
(+)-dactylol, the methyl substituent was still needed, and
the source of the stereochemistry was inexpensive.
total syntheses of both the racemic and enantiomerically pure
(
5) For some examples, see refs 1e and 3 and the following: (a)
Hoffmann, H. M. R.; Wagner, D.; Wartchow, R. Chem. Ber. 1990, 123,
131. (b) Hirano, T.; Kumagai, T.; Miyashi, T.; Akiyama, K.; Ikegami, Y.
2
J. Org. Chem. 1991, 56, 1907. (c) Samuel, C. J. J. Chem. Soc., Perkin
Trans. 2 1981, 736. (d) Hirano, T.; Kumagai, T.; Miyashi, T.; Akiyama,
K.; Ikegami, Y. J. Org. Chem. 1991, 56, 1907.
The synthesis is shown in Scheme 5. Formation of the
dianion from 10 and alkylation with 11 afforded 13 in 70%
(
6) Giguere, R. J.; Tassely, S. M.; Rose, M. I.; Krishnamurthy, V. V.
Tetrahedron Lett. 1990, 31, 4577.
7) Schmitz, F. J.; Hollenbeak, K. H.; Vanderah, D. J. Tetrahedron 1978,
4, 2719.
8) (a) Gadwood, R. C. J. Chem. Soc., Chem. Commun. 1985, 123. (b)
Paquette, L. A.; Ham., W. H.; Dime, D. S. Tetrahedron Lett. 1985, 26,
983. (c) Hayasaka, K.; Ohtsuka, T.; Shirahama, H.; Matsumoto, T.
11
yield. Removal of the carbomethoxy group was effected
(
via a Krapcho procedure and gave the ketone 14 in 94%
3
12
yield. Past experience suggested that the chlorination of
(
4
(9) Marx, J. N.; Norman, L. R. J. Org. Chem. 1975, 40, 1602.
(10) Diene 11 was prepared using Evans’ oxazolidinone chemistry.
Details will be reported elsewhere.
(11) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082.
(12) (a) Krapcho, A. P. Synthesis 1982, 805. (b) Krapcho, A. P. Synthesis
1982, 843.
Tetrahedron Lett. 1985, 26, 873. (d) Gadwood, R. C.; Lett, R. M.; Wissinger,
J. E. J. Am. Chem. Soc. 1986, 108, 6343. (e) Feldman, K. S.; Wu, M.-J.;
Rotella, D. P. J. Am. Chem. Soc. 1990, 112, 8490. (f) Molander, G. A.;
Eastwood, P. R. J. Org. Chem. 1995, 60, 4559. (g) F u¨ rstner, A.; Langemann,
K. J. Org. Chem. 1996, 61, 8746.
2914
Org. Lett., Vol. 2, No. 18, 2000

The major isomer was converted to (+)-dactylol. Applica-
tion of the Simmons-Smith reaction afforded 15 in 95%
yield. Interestingly, the Baeyer-Villiger reaction of 15
Scheme 5
1
5
proceeded in an unexpected fashion. Treatment of 15 with
MMPP in DMF afforded a 4:1 mixture of two regioisomeric
compounds, the major isomer being that which resulted from
migration of the less substituted carbon atom. The factors
influencing the regiochemistry of this reaction are under
study. Separation and hydrogenation of the cyclopropane ring
gave 17 in 98% yield. The structure and relative stereo-
chemistry of 17 were established by single-crystal X-ray
analysis.
Hydrolysis of 17 and esterification of the resulting hydroxy
acid afforded hydroxy ester 18. Installation of the double
bond with the correct regiochemistry was accomplished using
1
6
3
POCl in HMPA. Saponification of the ester then gave the
corresponding acid. The overall yield for this four-step
sequence was 84%.
Oxidative decarboxylation of 19 initially proved trouble-
some. We wanted to use a carboxy inversion beginning with
1
7
the corresponding acid chloride, but this compound was
not easily prepared under standard conditions. We ultimately
succeeded by using DMF and phosgene in refluxing toluene
18
to effect complete acid chloride formation. In the presence
of pyridine and DMAP, this acid chloride reacted with
mCPBA in benzene at room temperature to afford a mixed
carbonate which upon reduction afforded (+)-dactylol in 50%
overall yield from 19. The spectral data, analytical data, and
rotation of the sample were consistent with those published
7
,8
for dactylol.
In summary, we have established a new approach to
stereocontrol in intramolecular 4 + 3 cycloaddition reactions
applicable to the synthesis of cyclooctanoids as demonstrated
by a synthesis of (+)-dactylol. Further fundamental studies,
applications, and new approaches to stereocontrol are under
consideration and will be reported in due course.
the ketone and cycloaddition steps could be coupled without
any intervening purification. We also found that some
desilylation with concomitant double bond migration oc-
curred during the cycloaddition process, and therefore the
crude cycloaddition product was subsequently desilylated
using tosic acid. Thus, chlorination of the lithium enolate of
Acknowledgment. This work was supported by the
National Science Foundation to whom we are grateful. We
thank the National Science Foundation for partial support
of the NMR (PCM-8115599) facility at the University of
MissourisColumbia and for partial funding for the purchase
of a 500 MHz spectrometer (CHE-89-08304) and an X-ray
diffractometer (CHE-90-11804). Special thanks go to Dr.
Charles L. Barnes for acquisition of X-ray data.
13
14 with triflyl chloride followed by exposure of the resultant
chloroketone to triethylamine in a 1:1 mixture of trifluoro-
ethanol and ether gave a mixture which was treated with
tosic acid to afford 8 in an overall yield of 74%. Most
importantly, compound 8 was formed as a mixture of two
isomers in a ratio of 25:1, supporting the model for the
1
4
stereochemical outcome which we had developed. This
compares quite favorably with the diastereoselection ob-
served by Giguere and co-workers in the preparation of 6.
Supporting Information Available: 1H and 13C NMR
for 7-8 and 14-19. Tables of crystal data for 17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
13) Wender, P. A.; Holt, D. A. J. Am. Chem. Soc. 1985, 107, 7771.
(14) The ratio was determined by integration of the olefinic region of a
OL006390B
crude reaction mixture containing 8 and what appeared to be a single
additional cycloadduct (500 MHz). This minor product has not been isolated
or characterized.
(16) Trost, B. M.; Jungheim, L. N. J. Am. Chem. Soc. 1980, 102, 7910.
(17) (a) Denney, D. B.; Sherman, N. J. Org. Chem. 1965, 30, 3760. (b)
Kienzle, F.; Holland, G. W.; Jernow, J. L.; Kwoh, S.; Rosen, P. J. Org.
Chem. 1973, 38, 3440. (c) Danishefsky, S.; Tsuzuki, K. J. Am. Chem. Soc.
1980, 102, 6893. (d) Majetich, G.; Hull, K. Tetrahedron 1987, 43, 5621.
(18) Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents;
CRC: Boca Raton, 1994.
(
15) Reagent, ratio 16:isomer, solvent, T (°C), time, yield: (a) mCPBA/
NaHCO3, 6:1, CH2Cl2, rt, 5 days, 67%; (b) TFAA/H2O2, 5:1, CH2Cl2, 0
C-rt, 3 days, 36%; (c) mCPBA/TFA, 4:1, CH2Cl2, 0 °C-rt, 48 h, 53%;
d) peracetic acid/NaOAc, 9:1, AcOH, rt, 48 h, 31%; (e) MMPP, 4:1, DMF,
°
(
rt, 48 h, 84%.
Org. Lett., Vol. 2, No. 18, 2000
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